WEBVTT

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Prof: I'd like to
welcome you back,

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and hope that you all had
really good breaks.

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We'll be talking this week
about malaria,

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both today and on Wednesday.

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And I think I may be saying a
couple of things that you may

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find surprising.

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I suppose--this may be an
assumption--

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that when I mention malaria,
that most of you think of it as

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an exotic tropical disease,
and probably think that it's

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very distant from us,
and has relatively little to do

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with the modern world,
or with modern history,

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and probably nothing at all to
do with the United States and

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with those of us here.

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But the point I'm wanting to
make, this time and next,

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is that the reality of malaria
is quite different from that;

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that when we've come to talk
about this disease,

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I could say that of all human
diseases it's one of the oldest;

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and some question,
a question that some of you

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might ask me,
is of all the diseases in our

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course,
which is the one that,

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in the aggregate,
has caused the most human

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suffering and death?

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And I think that of all of the
diseases in our course,

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it's probably malaria which has
that primacy.

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The relationship of human
beings to malaria has been so

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close,
and so extensive,

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that we could also say that we,
as a species,

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and malaria,
as a disease,

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have evolved together,
and that the human genome bears

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the imprint of our experience
with malaria.

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Good examples of that are a
couple of genetic diseases that

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I'd like to mention,
one that may be familiar to you

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also,
one being sickle-cell anemia,

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a second being thalassemia,
and a third being what's called

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Duffy negativity.

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Now, all of these are genetic
diseases,

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and they have in common the
feature that there's a

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difference between the trait
which--

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it's a recessive in all three
cases,

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the recessive features.

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And, so, a heterozygote--that
is, a person who has just one X

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chromosome,
rather than X and Y,

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expressing the trait for the
disease--

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enjoys a protection from
malaria.

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But if, in fact,
you are a homozygote and have

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it on both X and Y chromosomes,
and you develop the syndrome

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for sickle-cell anemia,
instead you have a terrible

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disease that leads to--
it causes sickle cell--it

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affects the quality of the
hemoglobin and the red cells,

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and therefore it leads to
anemia, occlusion of blood

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vessels,
sometimes hypoxia,

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and serious respiratory
diseases.

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So, it's a fatal illness in
many cases.

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But if you have the trait,
then in a highly malarial area

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you have a great selective
advantage in enjoying a great

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deal of resistance or immunity.

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In terms of human evolution,
in intensely malarial areas

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there was a strong Darwinian
pressure for the retention of

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the sickle cell trait.

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The same would be true of
thalassemia,

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which affects not the quality
of the red cells but rather

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their quantity,
and leads to again terrible

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complications in homozygotes,
and with asthma and terrible

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anemia,
or Duffy negativity,

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which is another genetic
disease that leads again to

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terrible diseases.

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Another feature of malaria,
apart from the fact that our

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genome has actually been
strongly influenced by our

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history with malaria,
is that until very recently it

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extended more or less across the
globe,

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affecting not only the tropics
in Africa,

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Asia and South America,
but also the north,

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including most of Europe and
North America.

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So, I thought I'd show you a
map of malaria in the United

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States in the nineteenth
century,

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just to give you an idea--this
is 1882--

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to show how extensively
prevalent it was in this

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country,
as recently as the late

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nineteenth century.

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And indeed it comes up--Oliver
Wendell Holmes wrote a book on

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malaria in New England.

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This is a map of 1912,
when it's receded a great deal

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and is primarily a disease of
the South.

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But remember that it had a
major impact on public health in

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this country,
until the end of the Second

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World War,
which is when it was eradicated

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in the United States.

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It's sobering to remember,
for example,

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that the Centers for Disease
Control,

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the CDC, in Atlanta,
was originally founded as an

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anti-malarial agency,
and that the disease played a

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major role in the settlement of
the West,

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and in the economic and social
development of the South.

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And if you read Mark Twain,
for example,

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you can read a great deal about
shivering along the banks of the

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Mississippi River.

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In terms of our discussion of
relationship of diseases to the

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big picture of history,
malaria is also one of the

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diseases that I think helps us
to make the case most

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effectively.

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Malaria, it's now believed,
played a major part in the

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fall,
for example,

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of the Roman Empire,
when an epidemic of

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falciparum malaria led to
the disruption of agriculture

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and the Roman Legions.

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And I'm not trying to say that
malaria caused the downfall of

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the Roman Empire.

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I'm saying that it was a major
factor,

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leading to the kinds of
military problems and social

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dislocation that we can't ignore
in discussing that major series

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of events.

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It's led to major impacts on
the outcome and on the conduct

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of warfare.

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One need go back only to the
Second World War,

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when malaria was a major
preoccupation of the armies on

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both sides of the conflict.

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It had an enormous role and
impact on European expansion and

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colonization,
and one of the great challenges

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to colonial expansion,
in the Indian subcontinent,

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and in Africa,
was what to do about the

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problem of malaria.

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It's affected the pattern of
human habitation and settlement,

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the way that cities and towns
are built across the landscape,

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where human habitation often
was a form of prophylaxis for

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malaria,
and people lived far from

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swampy areas,
and often on high ground,

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above dangerous wetlands low
down.

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Malaria is also a major factor
in economic development and

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under-development today,
in ways that we'll be

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discussing.

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A decisive factor in its
prevalence, and in its history,

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has always been the
relationship of human beings to

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agriculture and the environment;
that is to say that intensive

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forms of agriculture,
with modern livestock raising

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practices,
modern crop rotations,

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water management,
ecological sanitation,

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with improved housing and
conditions of diet,

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wages and clothing,
have led, wherever they've been

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introduced,
to a spontaneous recession of

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malaria and much better health
outcomes.

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And this has been a major
factor in the divergence between

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the global North and the global
South;

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the North with modernized
intensive systems of

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agriculture,
and in the South instead the

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persistence of extensive forms
of practice that are conducive,

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for reasons we'll be examining,
to the transmission of malaria.

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So, malaria both reflects and
reinforces developmental

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differences and disparities.

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Now, let's remember that
malaria is vitally important in

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our world today.

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Let me give you an example of
some of the pictures that

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represent the global burden of
malaria,

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and let me show you a map of
where malaria is prevalent

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today;
that is, in the twenty-first

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century.

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Indeed, at the moment,
one can say the statistics are

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extraordinary.

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About 500,000 people become
seriously ill of malaria every

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year.

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Approximately a million people
die of it,

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the majority of them being
children under five,

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and pregnant women,
concentrated particularly in

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Sub-Saharan Africa.

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In fact, one can say that a
child dies of malaria,

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in Africa today,
every thirty seconds,

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making this disease a global
public health emergency,

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along with HIV/AIDS and
tuberculosis.

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Let's look at more particularly
the areas.

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This is the epicenter,
if you like,

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of the present day resurgence
of malaria as a major,

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major public health problem.

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And there are--malaria kills
3,000 children every day of the

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year.

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The burden of malaria though is
greater than statistics for

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mortality and morbidity suggest.

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It is, for example,
one of the worst possible

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complications of pregnancy.

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It leads to high rates of
miscarriage;

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to maternal death through
hemorrhaging and severe anemia,

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and all of the sequelae that
follow from severe low birth

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rate.

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Malaria also can be transmitted
vertically;

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that is, trans-plancentally,
from mother to fetus,

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and can lead to the birth of
infants who are congenitally

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infected.

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We also need to remember,
as we'll say in a moment,

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that malaria is a major
immunosuppressive disease,

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and its victims therefore are
highly susceptible to other

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opportunistic infections;
especially respiratory

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infections, tuberculosis,
influenza, pneumonia.

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In those areas of the tropical
world where malaria is

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hyper-endemic,
and transmission continues

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throughout the year,
the population at risk can be

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infected,
re-infected and super-infected

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every single year.

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If the victims of malaria
survive, they possess a

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painfully acquired immunity.

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But it comes at a terrible
price, because repeated bouts of

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malaria lead to severe
neurological deficit and

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cognitive impairment.

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The results are ineradicable
poverty, illiteracy and

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compromised economic growth,
a stunted development of civil

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society and political
instability.

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We'll be talking in a moment
about Ronald Ross,

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who was the Nobel Laureate,
who was one of two people who

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discovered the mosquito theory
of transmission for disease.

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And he wrote,
quite movingly,

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that those malaria doesn't--
in areas where malaria is

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prevalent--
"those it doesn't kill it

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enslaves."

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Malaria, in other words,
in our present world,

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is a major contributor to
inequalities between North and

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South,
and to the economic and

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political international
dependency of third-world

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countries in the tropical world.

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Well, let's talk about
the--malaria also will be of

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interest to us because it's an
extremely complex disease,

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and so we need to spend a
little bit of time talking about

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how it's transmitted,
and about its effects on the

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human body,
in order, after that,

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to talk about how the
discoveries that led to our

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understanding of it,
and to the impact on society

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and on history.

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Until the end of the nineteenth
century, malaria was thought to

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be explained by a theory that
you already know,

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by miasmatism.

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In other words,
malaria was a form of bad air.

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In fact, that's what the word
means, from the Italian

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mala, bad,
and aria,

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air.

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So, malaria was bad air that
somehow a susceptible person

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inhaled,
and it got in his or her body,

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or was absorbed,
perhaps, through the pores of

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the skin,
and led, in susceptible people,

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to this terrible fever.

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It was also sometimes called
paludisme, from the word for

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swamp;
so it was swamp fever.

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So, the disease then was
absorbed or breathed in,

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in some way.

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In fact, malaria isn't one
disease.

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It's a family of four different
diseases, caused by a parasite,

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with an extremely complex
lifecycle.

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The parasite is known as a
plasmodium, and there are four

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species of plasmodium that cause
human malaria.

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And I have them on your handout.

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They're Plasmodium
falciparum,

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Plasmodium vivax,
Plasmodium malariae,

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and Plasmodium ovale.

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For the purposes here,
the first two,

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Plasmodium falciparum
and Plasmodium vivax,

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are the most important,
medically and historically,

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and the ones we'll be talking
about mostly.

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Now, the plasmodia differ
fundamentally from the other

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microbial pathogens we've
examined so far in the course--

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bacteria, for example,
and viruses--

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in that they're much more
complex life forms,

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with complex lifecycles that we
need to unravel.

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Plasmodia were discovered in
1884 by Alphonse Laveran--there

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he is--a French Army doctor
working in Algeria.

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It turns out that the plasmodia
don't exist free in the

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environment at any stage of
their lives.

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Instead, they're adapted to
live either in the body of human

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beings, or in the gut of certain
species of mosquitoes.

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And--there we are--this is an
anopheles mosquito doing its

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thing;
that is to say,

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having a blood meal,
which is the way that malaria

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is transmitted from person to
person.

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The plasmodia--this is again,
in a more schematic way,

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it gets the point across about
the relationship of human beings

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and the mosquito.

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Plasmodia migrate in the body
of the insect to the salivary

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glands in the biting apparatus.

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So, a biting mosquito,
like this one,

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is in effect an extremely
efficient vector.

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It's sometimes referred to as a
flying syringe,

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because what it does,
the mosquito does,

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is to inoculate the plasmodia
directly into the bloodstream of

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the host.

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At this stage the
parasite--we'll move to look at

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what happens next.

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The first thing we have is the
mosquito taking a blood meal and

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inoculating the plasmodia
directly into the bloodstream of

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the unfortunate victim.

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At that stage--and here we'll
see one of the points about the

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plasmodia,
is that it undergoes a series

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of morphological changes in
becoming distinct stages in its

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life,
both in the human body and in

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the body of the insect.

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Initially when it's injected,
it's known as a sporazoite,

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and what it does next is it
migrates,

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after just a few hours after
inoculation--

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say you were bitten right now,
within a few hours the

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plasmodia in your bloodstream
would have migrated to your

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liver.

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And this begins the incubation
period in which the plasmodium

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reproduces--that is,
asexually--in the liver.

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And you see its reproduction.

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And then after just a number of
days or weeks,

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it's released again now in a
new phase, this time known as a

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merozoite, into the bloodstream.

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So, it returns at that point to
the bloodstream.

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One of the points of the
migration to the liver is that

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when it's in the liver,
it's safely beyond the

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detection of the human immune
system,

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and so it reproduces safely in
the liver and then emerges,

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much more numerous,
into the bloodstream in a new

21:14.419 --> 21:17.189
phase in its lifecycle.

21:17.190 --> 21:23.010
At this point in the
bloodstream what happens is that

21:23.006 --> 21:26.756
the merozoites--
that's what they're now called,

21:26.762 --> 21:29.352
the new name of the parasite
for that phase--

21:29.348 --> 21:36.448
it enters into--it attaches
itself to and enters into red

21:36.453 --> 21:40.263
blood cells or erythrocytes.

21:40.259 --> 21:44.569
Once safely inside the red
blood cell--

21:44.568 --> 21:48.318
again it's not detected by the
immune system--

21:48.318 --> 21:54.418
it reproduces asexually--and
you can see it doing so--

21:54.420 --> 21:59.780
until at a certain point it has
destroyed the red blood cell and

21:59.775 --> 22:04.785
ruptures the red blood cell,
and the parasites return once

22:04.788 --> 22:06.918
again to the bloodstream.

22:06.920 --> 22:09.810
I have--this is a picture.

22:09.808 --> 22:14.238
These are of the--by electron
microscope--

22:14.240 --> 22:18.510
of the actual rupturing of red
blood cells,

22:18.509 --> 22:21.979
and the emergence,
once gain, of the parasites

22:21.981 --> 22:27.021
that have just reproduced,
returning to the open

22:27.017 --> 22:28.747
bloodstream.

22:28.750 --> 22:33.320
At that point,
the much more numerous

22:33.320 --> 22:41.450
merozoites keep repeating this
process of invading red cells,

22:41.450 --> 22:45.930
reproducing,
destroying the red blood cells,

22:45.930 --> 22:49.860
and then bursting them at
periodic intervals.

22:49.858 --> 22:54.868
The interval of time that it
takes is determined by the

22:54.865 --> 22:57.085
species of plasmodium.

22:57.088 --> 23:01.198
For Plasmodium
falciparum and vivax,

23:01.204 --> 23:03.814
it's every forty-eight hours.

23:03.808 --> 23:08.618
And so for Plasmodium
malariae,

23:08.618 --> 23:11.868
it's every seventy-two.

23:11.868 --> 23:17.548
Now, eventually,
among the brood of merozoites--

23:17.548 --> 23:23.888
that is, let's see,
again--after it's gone through

23:23.892 --> 23:29.612
a number of cycles,
they produce among their

23:29.609 --> 23:36.069
offspring what are called--
it's a new morphologically

23:36.067 --> 23:40.247
different stage in the
lifecycle,

23:40.250 --> 23:45.480
and that is gametocytes,
that are male and female;

23:45.480 --> 23:47.790
and these are in the open
bloodstream.

23:47.788 --> 23:52.908
And then the next anopheline
mosquito that takes a blood

23:52.913 --> 23:56.743
meal,
as it does so it sucks up the

23:56.737 --> 24:03.527
male and female gametocytes that
reproduce sexually this time--

24:03.528 --> 24:09.928
we see them here--in the gut,
in the body of the female

24:09.928 --> 24:13.958
mosquito,
and then that begins the phase

24:13.961 --> 24:18.661
of life in the body of the
mosquito where once again we

24:18.663 --> 24:23.283
find it reproduces;
and eventually it leads to the

24:23.275 --> 24:27.765
production of sporozoites that
migrate, once again,

24:27.768 --> 24:32.258
to the biting apparatus,
the salivary glands of the

24:32.260 --> 24:33.520
mosquito.

24:33.519 --> 24:37.759
The mosquito again takes an
infective bite and then--

24:37.759 --> 24:40.609
in its next blood meal--and the
whole cycle,

24:40.608 --> 24:46.488
this complex cycle of both
asexual reproduction in the body

24:46.494 --> 24:49.844
of man,
and sexual reproduction in the

24:49.842 --> 24:55.552
body of the mosquito,
the cycle is then complete.

24:55.548 --> 25:04.878
Now, let's return for a second
to the plasmodia and to the

25:04.876 --> 25:06.346
insect.

25:06.348 --> 25:12.658
And let me just deal with the
fact that in order--

25:12.660 --> 25:18.960
the reason that the female--and
it's only female anophelines

25:18.961 --> 25:23.341
that take blood meals on human
beings--

25:23.338 --> 25:29.148
and the reason that the female
anopheline does that is that it

25:29.146 --> 25:34.666
needs blood in order to mature
its eggs and to lay them.

25:34.670 --> 25:41.880
Having taken a blood meal,
she's able to mature her eggs,

25:41.880 --> 25:47.780
and at that point lays them in
water,

25:47.779 --> 25:50.529
and they pass through the cycle
of larvae,

25:50.529 --> 25:56.389
pupae, and then the adult
mosquito known as an imago.

25:56.390 --> 26:00.130
Now, what happens at that point?

26:00.130 --> 26:03.770
It takes about a week for the
eggs to develop as larvae,

26:03.769 --> 26:08.399
pupae and then adult
mosquitoes, and then the

26:08.403 --> 26:14.623
mosquito is ready to take flight
and to visit you and me.

26:14.618 --> 26:19.758
From the breeding site to the
blood meal, the anopheles

26:19.759 --> 26:25.659
mosquitoes have delicate wings
and are normally weak flyers.

26:25.660 --> 26:30.600
So, normally she flies about no
more than three kilometers or

26:30.598 --> 26:32.738
so, from her birthplace.

26:32.740 --> 26:38.800
Most species of anopheles avoid
sunlight, that dries up their

26:38.800 --> 26:42.540
wings, and they avoid strong
winds.

26:42.538 --> 26:46.228
But as they take flight,
they're able to orient

26:46.230 --> 26:49.680
themselves to places of human
settlement.

26:49.680 --> 26:50.300
Why?

26:50.298 --> 26:57.388
Because on their antennae there
are sensors that are highly

26:57.393 --> 27:02.533
stimulated by carbon dioxide in
the air.

27:02.528 --> 27:08.228
And, so, this--the carbon
dioxide plume arising from human

27:08.230 --> 27:13.930
settlements and human bodies,
enables the mosquitoes to be

27:13.930 --> 27:16.130
attracted to them.

27:16.130 --> 27:22.160
Having arrived at closer range,
the mosquitoes then detect,

27:22.163 --> 27:27.263
with other sensors,
odors emanating from sweat.

27:27.259 --> 27:30.189
They're also attracted by light.

27:30.190 --> 27:35.040
And then at close range they
finally use their vision to

27:35.037 --> 27:40.587
settle on the site of the body
most suitable for their feast.

27:40.588 --> 27:45.528
And human beings cooperate in
this enterprise in that

27:45.527 --> 27:50.557
anopheline mosquitoes feast
between dusk and dawn,

27:50.558 --> 27:53.808
and they thereby attack
sleeping bodies,

27:53.809 --> 27:57.079
lying mostly motionless.

27:57.078 --> 28:02.008
Now, when you hear the buzz of
the harmless culex mosquito that

28:02.012 --> 28:06.552
buzzes noisily around you and
attracts your attention,

28:06.548 --> 28:10.878
you can be happy,
because most anophelines that

28:10.880 --> 28:16.530
transmit malaria are silent and
therefore don't disturb their

28:16.528 --> 28:17.468
hosts.

28:17.470 --> 28:23.630
You're probably wondering,
how is it that transmission is

28:23.630 --> 28:30.120
maintained if the vast majority
of mosquitoes don't transmit

28:30.118 --> 28:31.438
malaria?

28:31.440 --> 28:35.940
Only the females of certain
species of anophelines--

28:35.940 --> 28:40.850
and I've included two on your
handout as being most important

28:40.846 --> 28:46.416
to us: Anopheles gambiae,
which would be my candidate for

28:46.424 --> 28:51.334
the most deadly insect for human
beings on our planet,

28:51.328 --> 28:53.998
and Anopheles
labranchiae,

28:54.001 --> 28:58.681
which was one of the most
important vectors of malaria in

28:58.680 --> 29:01.520
Europe and in parts of Africa.

29:01.519 --> 29:06.589
You're probably wondering if a
female anopheline mosquito lives

29:06.593 --> 29:11.053
on average just a few weeks,
and needs to be infected

29:11.048 --> 29:14.408
herself before transmitting the
disease,

29:14.410 --> 29:16.790
how can transmission be
maintained?

29:16.788 --> 29:19.678
Well, there's a couple of facts
that we need to remember.

29:19.680 --> 29:25.490
First, is the vast numbers of
mosquitoes involved in areas

29:25.494 --> 29:28.254
where malaria is endemic.

29:28.250 --> 29:32.280
In most areas of high
endemicity, no more than two

29:32.278 --> 29:36.638
percent or so of female
mosquitoes are infected at any

29:36.635 --> 29:37.865
given time.

29:37.868 --> 29:42.208
But on average,
a human being can be bitten

29:42.210 --> 29:45.310
thousands of time in a year.

29:45.308 --> 29:49.488
And it's also true that an
insect like Anopheles

29:49.490 --> 29:54.340
gambiae is famished and
doesn't feed a single time,

29:54.338 --> 29:58.398
but having entered a place of
human settlement feasts

29:58.404 --> 30:02.094
repeatedly,
moving from one body to

30:02.090 --> 30:08.290
another, thereby ensuring that
in crowded conditions one

30:08.288 --> 30:14.938
malarial patient is a major
source of danger to all of those

30:14.938 --> 30:17.528
around him or her.

30:17.528 --> 30:22.268
Well, that's the story from the
standpoint of the mosquito.

30:22.269 --> 30:24.629
What happens to the human
victim?

30:24.630 --> 30:28.030
What are the symptoms of
malaria?

30:28.028 --> 30:34.818
How does the disease have its
impact on the human body?

30:34.818 --> 30:40.958
After the incubation period,
symptoms begin when the

30:40.960 --> 30:47.820
plasmodia have achieved a
critical threshold number in the

30:47.823 --> 30:49.753
bloodstream.

30:49.750 --> 30:55.950
It's then that the classical
symptoms of malaria begin,

30:55.948 --> 30:58.128
with their onset.

30:58.130 --> 31:06.080
Now, let's remember--return to
our diagram.

31:06.078 --> 31:11.678
This process of reproduction,
of entering--

31:11.680 --> 31:17.730
that is to say the parasite
enters the blood cell,

31:17.730 --> 31:21.890
reproduces, bursts the blood
cell and returns to the

31:21.886 --> 31:25.956
bloodstream--
occurs simultaneously for an

31:25.961 --> 31:30.141
entire brood throughout the
bloodstream.

31:30.140 --> 31:34.060
In other words,
this is happening at the same

31:34.056 --> 31:36.456
time throughout the body.

31:36.460 --> 31:40.550
And it's when there are
sufficient numbers of the

31:40.548 --> 31:45.738
parasite in the open bloodstream
that the immune system of the

31:45.743 --> 31:52.073
body can detect the parasite,
and it's then that symptoms

31:52.069 --> 31:52.959
begin.

31:52.960 --> 31:57.350
The term for malaria also--it
has many names,

31:57.352 --> 31:58.852
this disease.

31:58.848 --> 32:02.588
It was often called
intermittent fever.

32:02.588 --> 32:07.078
This process of synchronicity
was known as Golgi's law,

32:07.076 --> 32:11.976
after the malariologist Camillo
Golgi, who discovered it;

32:11.980 --> 32:17.040
and he talked about the
different timings of fever.

32:17.038 --> 32:20.488
Tertian fever,
that is to say,

32:20.492 --> 32:24.942
every forty-eight hours;
or Quartan fever,

32:24.944 --> 32:29.074
every seventy-two hours;
or Quotidian fever.

32:29.068 --> 32:34.588
You can also have a bout of
intense fever every twenty-four

32:34.592 --> 32:37.202
hours,
and that means that you have

32:37.202 --> 32:40.772
more than one species of
plasmodium in your bloodstream.

32:40.769 --> 32:45.639
You don't have to choose just
one, you can have several

32:45.638 --> 32:50.688
species and several types in
your bloodstream at once.

32:50.690 --> 32:53.180
If that occurs,
you can have fever,

32:53.183 --> 32:56.563
intermittent fever,
every twenty-four hours.

32:56.558 --> 33:01.758
The recurring classic symptoms
then are this intermittent

33:01.763 --> 33:06.413
fever, recurring at regular
intervals, like a train

33:06.411 --> 33:07.621
schedule.

33:07.618 --> 33:12.488
You have recurring paroxysms of
high temperature,

33:12.490 --> 33:16.930
plus chills,
profuse sweating,

33:16.931 --> 33:20.941
headache,
general malaise,

33:20.936 --> 33:26.216
exhaustion, and with it often
nausea,

33:26.220 --> 33:29.620
vomiting and diarrhea.

33:29.618 --> 33:35.168
The precise symptoms depend on
the species of plasmodium,

33:35.170 --> 33:39.510
and the most virulent is
Plasmodium falciparum,

33:39.509 --> 33:45.189
which causes the most frequent
life-threatening complications,

33:45.190 --> 33:51.400
and Plasmodium malariae
and ovale are the most

33:51.402 --> 33:52.142
mild.

33:52.140 --> 33:59.100
You see that by entering the
red and attacking red blood

33:59.095 --> 34:06.425
cells, the parasite initiates a
cascade of consequences.

34:06.430 --> 34:11.280
The red cells can become
misshapen,

34:11.280 --> 34:15.070
and they adhere to one another
in clumps,

34:15.070 --> 34:20.590
thereby causing blockages in
blood cells- blood vessels,

34:20.590 --> 34:25.330
that can be rapidly fatal,
depending on the organ that's

34:25.331 --> 34:26.281
affected.

34:26.280 --> 34:31.290
A frequent cause of mortality
is cerebral malaria,

34:31.289 --> 34:35.789
in which there are blockages in
the brain.

34:35.789 --> 34:38.859
But the heart can also be
affected, or the

34:38.860 --> 34:43.280
gastrointestinal system;
and if malaria attacks the

34:43.277 --> 34:48.587
gastrointestinal in particular,
it mimics the symptoms of

34:48.594 --> 34:50.404
Asiatic cholera.

34:50.400 --> 34:56.050
Destruction of the red blood
cells also is a cause of

34:56.052 --> 34:58.012
profound anemia.

34:58.010 --> 35:02.390
Another important symptom of
the disease is--

35:02.389 --> 35:06.789
and this is a child who's a
malaria patient,

35:06.789 --> 35:11.669
and what you see is a painful
and pronounced swelling of the

35:11.666 --> 35:12.406
spleen.

35:12.409 --> 35:18.459
This is one of the classic
signs of malarial infection.

35:18.460 --> 35:22.840
As I've said,
also malaria is terrible in its

35:22.835 --> 35:27.945
effects on pregnant women,
leading to hemorrhaging and

35:27.952 --> 35:31.812
miscarriage,
and also to congenital malaria

35:31.809 --> 35:35.049
with infants born with the
disease.

35:35.050 --> 35:42.020
Malaria also is a disease
that's a major immunosuppressive

35:42.016 --> 35:43.236
disease.

35:43.239 --> 35:48.479
It suppresses the immune system
of the body, and therefore gives

35:48.478 --> 35:52.138
rise to complications,
especially respiratory

35:52.137 --> 35:54.997
diseases;
as I mentioned earlier,

35:54.996 --> 35:58.006
pneumonia, influenza and
tuberculosis.

35:58.010 --> 36:03.060
So, we should say that the
tuberculosis emergency in the

36:03.063 --> 36:08.583
present day, and the malaria
emergency, are inter-locking and

36:08.576 --> 36:14.606
inter-related;
malaria provides the substratum

36:14.612 --> 36:20.272
for rampaging re-emerging
tuberculosis.

36:20.268 --> 36:25.438
I also said that recurring
bouts of malaria lead to

36:25.440 --> 36:30.940
neurological damage,
and in the worst cases to a

36:30.942 --> 36:36.642
state known as cachexia,
in which a person is

36:36.635 --> 36:42.005
indifferent to his or her
surroundings;

36:42.010 --> 36:47.210
is unable to learn to be
productive, to take part in

36:47.208 --> 36:48.838
civil society.

36:48.840 --> 36:53.800
Another feature of malaria is
that it can lead to relapses;

36:53.800 --> 36:56.560
that is, with Plasmodium
vivax.

36:56.559 --> 37:01.679
You remember that after the
plasmodium is injected into the

37:01.684 --> 37:05.224
bloodstream, it migrates to the
liver.

37:05.219 --> 37:09.659
Well in Plasmodium
vivax, the parasite does

37:09.663 --> 37:13.203
emerge, but not all of the
parasites.

37:13.199 --> 37:18.439
They continue to nestle in the
liver, and they're beyond the

37:18.438 --> 37:21.368
detection of the immune system.

37:21.369 --> 37:25.359
And they can then--even after
the patient thinks that he or

37:25.362 --> 37:29.632
she has recovered,
there can be a relapse when the

37:29.628 --> 37:31.688
plasmodia,
the parasites,

37:31.693 --> 37:34.963
re-emerge from the liver into
the bloodstream.

37:34.960 --> 37:39.150
This can be months later,
or even years later,

37:39.148 --> 37:41.938
after the initial infection.

37:41.940 --> 37:46.930
Immunity--that is,
once you've had lots of bouts

37:46.927 --> 37:53.187
of malaria, and you survive,
you develop a partial immunity,

37:53.186 --> 37:55.836
an acquired immunity.

37:55.840 --> 38:02.360
But it is short-term,
and it's also at considerable

38:02.364 --> 38:09.024
cost in terms of neurological
damage to the body.

38:09.018 --> 38:12.768
Well, the impact on society,
as you can imagine,

38:12.771 --> 38:15.711
is severe;
and we'll be talking about that

38:15.708 --> 38:16.408
next time.

38:16.409 --> 38:19.759
But it leads,
this disease--the symptoms,

38:19.760 --> 38:23.130
listing the symptoms,
helps us to understand that

38:23.130 --> 38:26.620
someone like this as an adult,
who's anemic,

38:26.617 --> 38:30.117
who has perhaps respiratory
diseases,

38:30.119 --> 38:34.619
moves painfully and slowly,
and is therefore not a

38:34.623 --> 38:39.223
productive worker in agriculture
or in industry.

38:39.219 --> 38:43.519
So, malaria leads to backward
systems of cultivation,

38:43.516 --> 38:46.986
low productivity,
and lack of investment in

38:46.987 --> 38:48.307
agriculture.

38:48.309 --> 38:53.079
It leads to the desertion of
whole- of some of the most

38:53.083 --> 38:57.063
fertile areas,
land, because it's particularly

38:57.063 --> 39:00.073
dangerous, and known to be so.

39:00.070 --> 39:04.470
It leads then to poverty,
to illiteracy.

39:04.469 --> 39:09.989
Indeed, malaria and poverty are
mutually reinforcing in a kind

39:09.987 --> 39:12.607
of vicious downward spiral.

39:12.610 --> 39:16.810
Poverty makes people vulnerable
to the disease.

39:16.809 --> 39:20.239
Poverty, that is,
makes people vulnerable because

39:20.239 --> 39:24.669
it causes them to live in poor
housing, overcrowded housing;

39:24.670 --> 39:31.520
housing that's porous and
vulnerable to flying insects.

39:31.518 --> 39:36.518
It also leads them to
occupational hazards in having

39:36.518 --> 39:41.418
to work in areas where the
disease is prevalent.

39:41.420 --> 39:45.340
It leads to poor diet,
which makes people more

39:45.344 --> 39:48.074
vulnerable;
to inadequate clothing,

39:48.068 --> 39:51.658
which makes them more
vulnerable to biting insects.

39:51.659 --> 39:56.039
But malaria,
in turn, then leads to further

39:56.036 --> 39:57.076
poverty.

39:57.079 --> 40:01.609
The burden of looking after the
ill, that falls on families and

40:01.606 --> 40:04.186
communities;
low productivity;

40:04.190 --> 40:06.910
low wages;
limited education.

40:06.909 --> 40:11.999
This was what Ross meant when
he says, "Those malaria

40:11.996 --> 40:15.026
doesn't kill,
it enslaves."

40:15.030 --> 40:20.590
Well, when was the mosquito
theory of transmission

40:20.594 --> 40:23.324
unraveled, and how so?

40:23.320 --> 40:28.890
The idea that mosquitoes were
involved in this disease wasn't

40:28.891 --> 40:30.471
at all obvious.

40:30.469 --> 40:35.149
It wasn't obvious because,
well, first of all scientists

40:35.150 --> 40:40.260
and physicians knew that there
are lots of places where there

40:40.255 --> 40:44.335
are gazillions of mosquitoes and
no malaria.

40:44.340 --> 40:48.810
It was also clear that
mosquitoes--there was no clear

40:48.811 --> 40:54.321
correlation between being bitten
by mosquitoes and developing the

40:54.317 --> 40:55.347
disease.

40:55.349 --> 41:01.489
And so the dominant theory in
the nineteenth century was of

41:01.489 --> 41:05.829
miasmatism as the cause of the
disease.

41:05.829 --> 41:10.559
The unraveling of the
disease--you'll remember this

41:10.557 --> 41:14.527
man, Patrick Manson,
the father of tropical

41:14.530 --> 41:15.760
medicine.

41:15.760 --> 41:20.640
He was also one of the figures
who was most closely associated

41:20.644 --> 41:24.094
in the development of tropical
medicine,

41:24.090 --> 41:27.660
and of the mosquito theory of
transmission,

41:27.659 --> 41:31.419
which he discovered for a
different disease called

41:31.422 --> 41:32.192
filaria.

41:32.190 --> 41:36.240
And then he had the idea that
perhaps if filaria could be

41:36.239 --> 41:40.579
transmitted by mosquitoes,
possibly malaria could as well.

41:40.579 --> 41:46.589
And so he joined forces--he
worked, Manson,

41:46.592 --> 41:48.312
in London.

41:48.309 --> 41:53.449
This is Ronald Ross,
who was a British military

41:53.449 --> 41:56.689
physician working in India.

41:56.690 --> 42:00.970
Now, India was a tremendously
important place in terms of

42:00.974 --> 42:01.744
malaria.

42:01.739 --> 42:06.269
Let me just--there was a book
that you might be interested in,

42:06.268 --> 42:09.308
and that I would recommend to
those of you who are,

42:09.309 --> 42:14.209
which is the correspondence
between Ronald Ross and Patrick

42:14.213 --> 42:17.683
Manson,
that led them to the discovery

42:17.681 --> 42:21.181
of the mosquito theory of
transmission.

42:21.179 --> 42:27.399
Now Ross worked in India,
and he noted that malaria,

42:27.396 --> 42:33.736
amongst the general population
of India in the 1890s,

42:33.735 --> 42:37.145
led to 5,000,000 deaths.

42:37.150 --> 42:42.720
And he said that it was the
greatest problem of public

42:42.717 --> 42:44.607
health in India.

42:44.610 --> 42:46.330
"I think on the
whole," he wrote,

42:46.329 --> 42:49.969
"that the Indian
population of 400,000,000,

42:49.969 --> 42:56.409
it causes directly or
indirectly 10,000 deaths a day.

42:56.409 --> 42:58.489
And apart from this amount of
sickness,

42:58.489 --> 43:02.119
malaria is, of all diseases,
the most important in

43:02.117 --> 43:05.007
political,
agricultural and military

43:05.005 --> 43:07.005
affairs,"
he wrote,

43:07.010 --> 43:10.790
"since it renders large
tracts of fertile land

43:10.793 --> 43:13.823
uninhabitable,
impedes cultivation,

43:13.820 --> 43:18.130
planting and public works,
and is the most fierce,

43:18.128 --> 43:22.438
vicious enemy that armies in
the field have to contend

43:22.436 --> 43:23.326
against.

43:23.329 --> 43:28.499
On the whole I think we're
justified in claiming that the

43:28.498 --> 43:33.298
malaria question is as important
as famine or bubonic

43:33.300 --> 43:34.870
plague."

43:34.869 --> 43:42.449
In India, what Ross and Manson
did was to discover--let's go

43:42.447 --> 43:48.867
back to our picture of the
lifecycle of malaria.

43:48.869 --> 43:54.319
They traced--through
microscopy, were able to detect

43:54.324 --> 43:59.784
in the body of the mosquito
after it had bitten,

43:59.780 --> 44:02.510
and they did experiments in
which they--

44:02.510 --> 44:07.400
among not human beings but
birds--and they discovered that

44:07.398 --> 44:12.548
it was possible to detect the
plasmodia responsible for avian

44:12.545 --> 44:15.135
malaria,
under the microscope,

44:15.141 --> 44:17.191
in the body of the mosquito.

44:17.190 --> 44:22.110
That was a first major insight,
that the mosquito was in some

44:22.114 --> 44:23.514
way implicated.

44:23.510 --> 44:28.990
But then they went further and
they followed the process by

44:28.985 --> 44:34.645
which it changed various phases
in the body of the insect and

44:34.648 --> 44:39.418
reproduced,
and they traced the migration

44:39.420 --> 44:45.830
of the parasite to the biting
apparatus of the mosquito.

44:45.829 --> 44:50.229
And then they were able to take
healthy birds and have

44:50.228 --> 44:53.768
mosquitoes,
who were known to be infected,

44:53.769 --> 44:57.389
feast on them,
and to produce malaria

44:57.385 --> 45:00.045
experimentally on birds.

45:00.050 --> 45:03.020
And, so, in 1898,
if you were reading this

45:03.023 --> 45:06.623
correspondence,
there's a eureka moment in

45:06.619 --> 45:11.909
which Ross announces that he's
discovered the mosquito theory

45:11.907 --> 45:14.977
of transmission,
and proved it.

45:14.980 --> 45:19.410
And he claims that he feels
like Captain Cook,

45:19.411 --> 45:23.551
the explorer,
or possibly like Napoleon.

45:23.550 --> 45:27.520
And he was not,
however, a naturalist,

45:27.518 --> 45:32.618
and he didn't know about the
speciation of mosquitoes,

45:32.619 --> 45:36.749
and the mosquitoes he
described, he described as

45:36.751 --> 45:39.681
dappled,
brindled or light brown.

45:39.679 --> 45:42.949
He didn't know about the
species of Anopheles

45:42.954 --> 45:44.144
mosquitoes.

45:44.139 --> 45:48.489
It's at this point that we
should mention then a second

45:48.489 --> 45:52.049
major figure--
oops, anyway we'll see--it

45:52.052 --> 45:56.092
doesn't matter--
Giovanni Battista

45:56.088 --> 46:01.578
Grassi, who was the next figure
in the development of the

46:01.579 --> 46:08.529
mosquito theory of transmission,
and he does so for human beings.

46:08.530 --> 46:14.210
And what he does is he
discovers that it's possible--

46:14.210 --> 46:19.120
in a place called Capaccio he
takes railroad workers,

46:19.119 --> 46:23.179
in the midst of a major malaria
outbreak in the summer,

46:23.179 --> 46:26.899
and he introduces one variable
in their lives,

46:26.900 --> 46:30.340
from a control group of
railroad workers and the

46:30.335 --> 46:35.485
surrounding peasantry;
and that is that one group he

46:35.494 --> 46:42.194
has living from dusk until dawn
in well-screened houses;

46:42.190 --> 46:46.860
and this difference protecting
them from the one factor,

46:46.858 --> 46:51.778
which is from the bites of
mosquitoes, prevents their being

46:51.782 --> 46:53.822
contracting malaria.

46:53.820 --> 46:56.920
This was one place in which he
did that.

46:56.920 --> 47:01.290
And then he also did a
different experiment,

47:01.291 --> 47:06.781
which was to use quinine,
which kills malaria parasites

47:06.782 --> 47:09.632
in the open bloodstream.

47:09.630 --> 47:14.290
He gave it prophylactically to
a series of workers,

47:14.289 --> 47:17.229
as a control group,
in a place like Ostia,

47:17.230 --> 47:21.970
during the summer malaria
season, and found that he could

47:21.971 --> 47:26.201
protect them as well from
malaria by establishing a

47:26.204 --> 47:31.374
chemical barrier between the
mosquitoes and human beings.

47:31.369 --> 47:35.369
And then he took the further
step of actually taking

47:35.369 --> 47:39.839
mosquitoes who were known to
have feasted on people ill of

47:39.840 --> 47:43.040
malaria,
and took them to a hospital in

47:43.041 --> 47:46.171
Rome known as the Santo Spirito
Hospital,

47:46.170 --> 47:52.010
where he had a volunteer on the
second floor who was in a room

47:52.010 --> 47:57.090
where at night they released
hundreds of intentionally

47:57.085 --> 48:01.905
infected mosquitoes,
and a couple of weeks later

48:01.907 --> 48:06.667
they had their eureka moment
when he had a spike and a

48:06.672 --> 48:10.772
temperature of 104,
and they knew that they had

48:10.773 --> 48:15.223
successfully transmitted malaria
by human experimentation to

48:15.219 --> 48:19.589
someone who had been healthy
until mosquitoes infected with

48:19.590 --> 48:23.510
the disease had been allowed to
feast upon him.

48:23.510 --> 48:31.140
So, this then happens between
1898 and 1901.

48:31.139 --> 48:35.859
And this then is a powerful
factor in the development of

48:35.855 --> 48:37.565
tropical medicine.

48:37.570 --> 48:42.540
But it also leads to programs
to combat malaria.

48:42.539 --> 48:46.409
Having discovered the pathogen
responsible to it,

48:46.409 --> 48:49.199
the plasmodia,
and the vector,

48:49.202 --> 48:54.302
female anopheles mosquitoes,
we see the development of

48:54.302 --> 48:58.362
public health programs to
destroy the disease--

48:58.360 --> 49:04.490
either by attacking the
plasmodia with chemical therapy,

49:04.489 --> 49:08.419
that is, through quinine;
or by killing mosquitoes,

49:08.423 --> 49:13.403
that is, vector control--the
idea of possibly being able to

49:13.398 --> 49:15.198
eradicate malaria.

49:15.199 --> 49:19.429
And next time what I'd like to
do is to follow the practical

49:19.425 --> 49:23.215
application then of the
discoveries we've talked about

49:23.222 --> 49:25.842
today,
about the life cycle of

49:25.835 --> 49:29.085
plasmodia and of anopheline
mosquitoes,

49:29.090 --> 49:32.930
and see how that leads to the
development of public health

49:32.925 --> 49:33.795
strategies.

49:33.800 --> 49:39.530
And I'd like to talk about how
those strategies are being used

49:39.525 --> 49:44.405
in the real world today to
combat this crisis of this

49:44.407 --> 49:47.597
dreadful vector-borne disease.

49:47.599 --> 49:52.999